Calcium hydroxide as an intracanal medication for postoperative pain during primary root canal therapy: A systematic review and meta-analysis with trial sequential analysis of randomised controlled trials.

OBJECTIVE: To evaluate the effectiveness of CH as an intracanal medicament compared to no dressing and / or other intracanal medicaments to control postoperative pain in patients with apical periodontitis requiring primary root canal therapy. MATERIALS AND METHODS: We conducted electronic searches in PubMed, EMBASE, Scopus and Cochrane Library, Open Gray, and Google Scholar. A structured Population-Intervention-Comparison-Outcome of the review was as follows: Population: adults who presented with apical periodontitis requiring primary root canal therapy; Intervention: CH intracanal medicament; Comparison: no dressing/other intracanal medicaments; Main Outcome: Postoperative pain. We assessed the risk of bias using Cochrane criteria. Our outcome measures were intensity of pain on a validated scale reported as mean and standard deviation. We performed meta-analysis using the random-effects model. We rated the quality of evidence using GRADE. RESULTS: We included 18 studies with 1192 participants. The overall risk of bias was moderate. We found a significant improvement in postoperative pain at 24 hours in favor of CH over no intracanal medication (4 trials, n = 226: standardised mean difference: -0.71; [95% confidence interval: -1.38, -0.03]; P = .04; I2= 78%; moderate certainty evidence). Ledermix (Lederle Germany) (steroid-antibiotic) and chlorhexidine were significantly more effective than CH for controlling pain at 72 hours postprocedure (low certainty evidence). Silver nanoparticles were more effective than CH at 6 and 24 hours and combinations of CH with dexamethasone or lidocaine HCl were significantly more effective than CH alone at improving postoperative pain. Substantial heterogeneity limits the robustness of findings. CONCLUSION: Limited evidence suggests that CH may be an effective intracanal medicament for controlling interappointment pain. Combination therapies appear to be more effective than using CH alone. Further research assessing the comparative effectiveness of interventions for managing postoperative pain following root canal therapy is warranted.

Naltrexone-bupropion (Mysimba) in management of obesity: A systematic review and meta-analysis of unpublished clinical study reports.

AIMS: To compare the benefits and harms of naltrexone-bupropion using evidence from clinical study reports. METHODS: We searched Food and Drug Administration and European Medicines Agency websites, PubMed, and Clinicaltrials.gov (May 2016) to identify pivotal trials; we then sent a freedom of information request to the European Medicines Agency (July 2016). We included pivotal, phase III placebo-controlled trials. We assessed the risks of bias using the Cochrane criteria, and the quality of the evidence using GRADE. We used a random-effects model for meta-analyses. RESULTS: Over a 27-month period (July 2016 to August 2018), we received 31 batches of clinical study report documents containing over 65 000 pages of data from 4 pivotal trials (n = 4536). Significantly more participants who took naltrexone-bupropion achieved ≥5% reduction in body weight: risk ratio (RR) = 2.1 (95% confidence interval 1.35-3.28), P = .001, GRADE = low, number needed to treat (NNT) to benefit = 5 (3-17); this represents a 2.53 kg (1.85-3.21) reduction in baseline body weight compared with placebo. Naltrexone-bupropion had significantly beneficial effects on other cardiovascular risk factors; however, the true effect sizes for these are uncertain because of incomplete outcome data. Naltrexone-bupropion significantly increased the risk of adverse events: RR = 1.11 (1.05-1.18, P = .0004, GRADE = low, NNT to harm = 12 7-27); serious adverse events: RR = 1.70 (1.38-2.1, P < .00001, GRADE = moderate, NNT to harm = 21 13-38); and discontinuation because of adverse events: RR = 1.92 (1.65-2.24, P < .00001, GRADE = moderate, NNT to discontinue treatment = 9 8-13). CONCLUSIONS: Naltrexone-bupropion significantly reduces body weight by a small amount but significantly increases the risk of adverse events. A rigorous process of postmarketing surveillance is required.

Correction to: Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature.

The original article [1] contains a minor error whereby the dates for year of first launch and year of first report of adverse reaction for iophendylate in e-Appendix Table 1 are mistakenly presented as 1946 and 1975 respectively.

Low-dose ketamine in painful orthopaedic surgery: a systematic review and meta-analysis.

BACKGROUND: Ketamine is a phencyclidine intravenous anaesthetic that blocks N-methyl-d-aspartate receptors and HCN channels in the CNS. Lately it has gained acceptance in a low-dose form, with studies showing an analgesic benefit in orthopaedic surgery. Our goal was to critically appraise and synthesise current evidence regarding use of low-dose ketamine in major, painful orthopaedic surgeries. METHODS: We conducted searches in Medline, Embase, Cochrane, and specialty journals for randomised controlled trials (RCTs) that compared low-dose ketamine to placebo. Primary outcomes included total opioid use, time to first opioid, and VAS pain scores. Meta-analyses were undertaken in RevMan software using a random effects model. We rated the quality of the evidence using the GRADE Working Group criteria. RESULTS: We included 20 studies across four subgroups for meta-analysis. The overall quality of the evidence was moderate. Ketamine significantly decreased total opioid use and pain scores (VAS) at 24 and 48 h (Opioid: standardised mean difference [SMD] -0.82 [-1.24, -0.40], p=0.0001, and -0.65 [-1.03,-0.27], p=0.0008; VAS: SMD -0.53 [-0.91, -0.15], p=0.006 and -0.60 [-1.05, -0.16], p=0.008), and delayed the time to first opioid dose (SMD 0.64 [0.01, 1.27], p=0.05). Results for nausea and hallucinations were equivocal, whereas results for chronic pain were inconclusive. The most prominent effects were seen in total joint operations. CONCLUSION: Low-dose ketamine is an effective adjuvant that decreases pain and opioid requirements in painful orthopaedic procedures, especially in the first 24 h after procedure. Future research should focus on arthroscopic procedures and the incidence of chronic pain.

Biomarkers for diagnosing serious bacterial infections in older outpatients: a systematic review.

BACKGROUND: The value of biomarkers for diagnosing bacterial infections in older outpatients is uncertain and limited official guidance exists for clinicians in this area. The aim of this review is to critically appraise and evaluate biomarkers for diagnosing bacterial infections in older adults (aged 65 years and above). METHODS: We searched Medline, Embase, Web of Science and the Cochrane Library, from inception to January 2018. We included studies assessing the diagnostic accuracy of blood, urinary, and salivary biomarkers in diagnosing bacterial infections in older adults. The QUADAS-2 tool was used to assess study quality. RESULTS: We identified 11 eligible studies of moderate quality (11,034 participants) including 51 biomarkers at varying thresholds for diagnosing bacterial infections. An elevated Procalcitonin (≥ 0.2 ng/mL) may help diagnose bacteraemia in older adults [+ve LR range 1.50 to 2.60]. A CRP ≥ 50 mg/L only raises the probability of bacteraemia by 5%. A positive urine dipstick aids diagnosis of UTI (+ve LR range 1.23 to 54.90), and absence helps rule out UTI (-ve LR range 0.06 to 0.46). An elevated white blood cell count is unhelpful in diagnosing intra-abdominal infections (+ve LR range 0.75 to 2.62), but may aid differentiation of bacterial infection from other acute illness (+ve LR range 2.14 to 7.12). CONCLUSIONS: The limited available evidence suggests that many diagnostic tests useful in younger patients, do not help to diagnose bacterial infections in older adults. Further evidence from high quality studies is urgently needed to guide clinical practice. Until then, symptoms and signs remain the mainstay of diagnosis in community based populations.

Postmarketing withdrawal of human medicinal products because of adverse reactions in animals: a systematic review and analysis.

PURPOSE: We have identified human medicinal products for which animal data were used as evidence for withdrawal, determined whether the adverse reactions were reported in humans, established whether confirmatory human studies were conducted, and explored the withdrawal patterns over time. METHODS: We searched the World Health Organization's Consolidated List of [Medicinal] Products, drug regulatory authorities' websites, PubMed, Google Scholar, and selected textbooks to identify medicinal products withdrawn from 1950 to June 2016. We included medicinal products for which animal data were specifically reported as a reason for withdrawal. We used a checklist adapted from the International Agency for Research on Cancer criteria to rate the evidence. RESULTS: In 37 cases, evidence from animals was the reason given for withdrawal between 1963 and 2000. Evidence of carcinogenicity was cited in 23 cases (62%). Limited evidence for harms occasioned withdrawal in over 80% of cases. In 11 cases (30%), the adverse drug reactions were subsequently reported in humans. In 5 instances (14%), formal studies were conducted in humans. The median interval to withdrawal following reports of adverse reactions was 2 years (IQR = 1-9 y). CONCLUSIONS: Regulatory authorities and drug manufacturers are likely to withdraw medicinal products quickly from the market when animal experiments suggest increased risks of cancers or congenital malformations. Human studies are seldom conducted when harms are suspected in animals. Future research should explore better methods of extrapolating harms data from animal research to humans.

The efficacy of supplementation with the novel medical food, Souvenaid, in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND AND RATIONALE: Certain nutritional supplements are being marketed for the management of Alzheimer's disease (AD), but the evidence for their effectiveness is not established. The objective of this review was to evaluate the evidence from randomized clinical trial (RCTs) examining the effect of Souvenaid in patients with AD. METHODS: We conducted electronic searches in Medline, Embase, PsychINFO, CINAHL, and The Cochrane Library. The reporting quality of the included studies was determined using the Cochrane collaboration tool for assessing the risk of bias. Two reviewers independently determined eligibility, assessed the reporting quality of included studies and extracted data. RESULTS: Three studies with a total of 1011 participants were included. All were of good reporting quality. Meta-analyses revealed non-significant differences in cognition (ADAS-cog scores MD: 0.08, 95% CI: -0.71 to 0.88) and function (ADCS-ADL scores MD: 0.36, 95% CI: -0.54 to 1.25) between Souvenaid and placebo. One study showed significant increase in neuropsychological test battery composite z-score with Souvenaid compared with placebo, and another reported significant improvement in delayed verbal recall for a subgroup of patients with very mild AD. There was no significant effect on global clinical function. No serious adverse events were observed. CONCLUSIONS: The evidence from published clinical trials does not show that supplementation with Souvenaid has beneficial effects on functional ability, behaviour, or global clinical change. Souvenaid may cause improvements in verbal recall in patients at early stages of AD. Few RCTs examining the effect of Souvenaid have been conducted, and they are all funded by same manufacturer. Future research should include using unified tools to measure cognition, function, and behaviour in AD.

Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review.

BACKGROUND: We identified anti-obesity medications withdrawn since 1950 because of adverse drug reactions after regulatory approval, and examined the evidence used to support such withdrawals, investigated the mechanisms of the adverse reactions, and explored the trends over time. METHODS: We conducted searches in PubMed, the World Health Organization database of drugs, the websites of drug regulatory authorities, and selected full texts, and we hand searched references in retrieved documents. We included anti-obesity medications that were withdrawn between 1950 and December 2015 and assessed the levels of evidence used for making withdrawal decisions using the Oxford Centre for Evidence-Based Medicine criteria. RESULTS: We identified 25 anti-obesity medications withdrawn between 1964 and 2009; 23 of these were centrally acting, via monoamine neurotransmitters. Case reports were cited as evidence for withdrawal in 80% of instances. Psychiatric disturbances, cardiotoxicity (mainly attributable to re-uptake inhibitors), and drug abuse or dependence (mainly attributable to neurotransmitter releasing agents) together accounted for 83% of withdrawals. Deaths were reportedly associated with seven products (28%). In almost half of the cases, the withdrawals occurred within 2 years of the first report of an adverse reaction. CONCLUSIONS: Most of the drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions. The reasons for withdrawal raise concerns about the wisdom of using pharmacological agents that target monoamine neurotransmitters in managing obesity. Greater transparency in the assessment of harms from anti-obesity medications is therefore warranted.

Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature.

BACKGROUND: There have been no studies of the patterns of post-marketing withdrawals of medicinal products to which adverse reactions have been attributed. We identified medicinal products that were withdrawn because of adverse drug reactions, examined the evidence to support such withdrawals, and explored the pattern of withdrawals across countries. METHODS: We searched PubMed, Google Scholar, the WHO's database of drugs, the websites of drug regulatory authorities, and textbooks. We included medicinal products withdrawn between 1950 and 2014 and assessed the levels of evidence used in making withdrawal decisions using the criteria of the Oxford Centre for Evidence Based Medicine. RESULTS: We identified 462 medicinal products that were withdrawn from the market between 1953 and 2013, the most common reason being hepatotoxicity. The supporting evidence in 72 % of cases consisted of anecdotal reports. Only 43 (9.34 %) drugs were withdrawn worldwide and 179 (39 %) were withdrawn in one country only. Withdrawal was significantly less likely in Africa than in other continents (Europe, the Americas, Asia, and Australasia and Oceania). The median interval between the first reported adverse reaction and the year of first withdrawal was 6 years (IQR, 1-15) and the interval did not consistently shorten over time. CONCLUSION: There are discrepancies in the patterns of withdrawal of medicinal products from the market when adverse reactions are suspected, and withdrawals are inconsistent across countries. Greater co-ordination among drug regulatory authorities and increased transparency in reporting suspected adverse drug reactions would help improve current decision-making processes.

Worldwide withdrawal of medicinal products because of adverse drug reactions: a systematic review and analysis.

We have systematically identified medicinal products withdrawn worldwide because of adverse drug reactions, assessed the level of evidence used for making the withdrawal decisions, and explored the patterns of withdrawals over time. We searched PubMed, the WHO database of withdrawn products, and selected texts. We included products that were withdrawn after launch from 1950 onwards, excluding non-human and over-the-counter medicines. We assessed the levels of evidence on which withdrawals were based using the Oxford Center for Evidence Based Medicine Levels of Evidence. Of 353 medicinal products withdrawn from any country, only 40 were withdrawn worldwide. Anecdotal reports were cited as evidence for withdrawal in 30 (75%) and deaths occurred in 27 (68%). Hepatic, cardiac, and nervous system toxicity accounted for over 60% of withdrawals. In 28 cases, the first withdrawal was initiated by the manufacturer. The median interval between the first report of an adverse drug reaction that led to withdrawal and the first withdrawal was 1 year (range 0-43 years). Worldwide withdrawals occurred within 1 year after the first withdrawal in any country. In conclusion, the time it takes for drugs to be withdrawn worldwide after reports of adverse drug reactions has shortened over time. However, there are inconsistencies in current withdrawal procedures when adverse drug reactions are suspected. A uniform method for establishing worldwide withdrawal of approved medicinal products when adverse drug reactions are suspected should be developed, to facilitate global withdrawals. Rapid synthesis of the evidence on harms should be a priority when serious adverse reactions are suspected.

Self-monitoring and self-management of oral anticoagulation.

BACKGROUND: The introduction of point-of-care devices for the management of patients on oral anticoagulation allows self-testing by the patient at home. Patients who self-test can either adjust their medication according to a pre-determined dose-INR (international normalized ratio) schedule (self-management), or they can call a clinic to be told the appropriate dose adjustment (self-monitoring). Increasing evidence suggests self-testing of oral anticoagulant therapy is equal to or better than standard monitoring. This is an updated version of the original review published in 2010. OBJECTIVES: To evaluate the effects on thrombotic events, major haemorrhages, and all-cause mortality of self-monitoring or self-management of oral anticoagulant therapy compared to standard monitoring. SEARCH METHODS: For this review update, we re-ran the searches of the Cochrane Central Register of Controlled Trials (CENTRAL), 2015, Issue 6, the Cochrane Library, MEDLINE (Ovid, 1946 to June week 4 2015), Embase (Ovid, 1980 to 2015 week 27) on 1 July 2015. We checked bibliographies and contacted manufacturers and authors of relevant studies. We did not apply any language restrictions . SELECTION CRITERIA: Outcomes analysed were thromboembolic events, mortality, major haemorrhage, minor haemorrhage, tests in therapeutic range, frequency of testing, and feasibility of self-monitoring and self-management. DATA COLLECTION AND ANALYSIS: Review authors independently extracted data and we used a fixed-effect model with the Mantzel-Haenzel method to calculate the pooled risk ratio (RR) and Peto's method to verify the results for uncommon outcomes. We examined heterogeneity amongst studies with the Chi(2) and I(2) statistics and used GRADE methodology to assess the quality of evidence. MAIN RESULTS: We identified 28 randomised trials including 8950 participants (newly incorporated in this update: 10 trials including 4227 participants). The overall quality of the evidence was generally low to moderate. Pooled estimates showed a reduction in thromboembolic events (RR 0.58, 95% CI 0.45 to 0.75; participants = 7594; studies = 18; moderate quality of evidence). Both, trials of self-management or self-monitoring showed reductions in thromboembolic events (RR 0.47, 95% CI 0.31 to 0.70; participants = 3497; studies = 11) and (RR 0.69, 95% CI 0.49 to 0.97; participants = 4097; studies = 7), respectively; the quality of evidence for both interventions was moderate. No reduction in all-cause mortality was found (RR 0.85, 95% CI 0.71 to 1.01; participants = 6358; studies = 11; moderate quality of evidence). While self-management caused a reduction in all-cause mortality (RR 0.55, 95% CI 0.36 to 0.84; participants = 3058; studies = 8); self-monitoring did not (RR 0.94, 95% CI 0.78 to 1.15; participants = 3300; studies = 3); the quality of evidence for both interventions was moderate. In 20 trials (8018 participants) self-monitoring or self-management did not reduce major haemorrhage (RR 0.95, 95% CI, 0.80 to 1.12; moderate quality of evidence). There was no significant difference found for minor haemorrhage (RR 0.97, 95% CI 0.67 to 1.41; participants = 5365; studies = 13). The quality of evidence was graded as low because of serious risk of bias and substantial heterogeneity (I(2) = 82%). AUTHORS' CONCLUSIONS: Participants who self-monitor or self-manage can improve the quality of their oral anticoagulation therapy. Thromboembolic events were reduced, for both those self-monitoring or self-managing oral anticoagulation therapy. A reduction in all-cause mortality was observed in trials of self-management but not in self-monitoring, with no effects on major haemorrhage.

Delays in the post-marketing withdrawal of drugs to which deaths have been attributed: a systematic investigation and analysis.

BACKGROUND: Post-marketing withdrawal of medicinal products because of deaths can be occasioned by evidence obtained from case reports, observational studies, randomized trials, or systematic reviews. There have been no studies of the pattern of withdrawals of medicinal products to which deaths have been specifically attributed and the evidence that affects such decisions. Our objectives were to identify medicinal products that were withdrawn after marketing in association with deaths, to search for the evidence on which withdrawal decisions were based, and to analyse the delays involved and the worldwide patterns of withdrawal. METHODS: We searched the World Health Organization's Consolidated List of [Medicinal] Products, drug regulatory authorities' websites, PubMed, Google Scholar, and textbooks on adverse drug reactions. We included medicinal products for which death was specifically mentioned as a reason for withdrawal from the market. Non-human medicines, herbal products, and non-prescription medicines were excluded. One reviewer extracted the data and a second reviewer verified them independently. RESULTS: We found 95 drugs for which death was documented as a reason for withdrawal between 1950 and 2013. All were withdrawn in at least one country, but at least 16 remained on the market in some countries. Withdrawals were more common in European countries; few were recorded in Africa (5.3%). The more recent the launch date, the sooner deaths were reported. However, in 47% of cases more than 2 years elapsed between the first report of a death and withdrawal of the drug, and the interval between the first report of a death attributed to a medicinal product and eventual withdrawal of the product has not improved over the last 60 years. CONCLUSIONS: These results suggest that some deaths associated with these products could have been avoided. Manufacturers and regulatory authorities should expedite investigations when deaths are reported as suspected adverse drug reactions and consider early suspensions. Increased transparency in the publication of clinical trials data and improved international co-ordination could shorten the delays in withdrawing dangerous medicinal products after reports of deaths and obviate discrepancies in drug withdrawals in different countries.

Antibiotics for preventing lower respiratory tract infections in high-risk children aged 12 years and under.

BACKGROUND: Lower respiratory tract infections (LRTIs) in young children account for 1.4 million deaths annually worldwide. Antibiotics could be beneficial in preventing LRTIs in high-risk children, and may also help prevent school absenteeism and work days missed by children and/or carers. While it is well documented that the efficacy of antibiotic prophylaxis for RTIs decreases over time, there are no reviews that describe the use of antibiotic prophylaxis to prevent LRTIs in high-risk children aged 12 years and under. OBJECTIVES: To assess the effectiveness and safety of antibiotic prophylaxis in the prevention of bacterial LRTIs in high-risk children aged 12 years and under. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 1) and the Database of Abstracts of Reviews of Effects (DARE), MEDLINE and MEDLINE In-Process (OvidSP) (1946 to 13 February 2015), EMBASE (OvidSP) (1974 to 12 February 2015), Science Citation Index Expanded (1945 to 13 February 2015) and Conference Proceedings Citation Index-Science (Web of Science Core Collection) (1990 to 13 February 2015). We searched for ongoing studies on ClinicalTrials.gov and the World Health Organization ICTRP. We handsearched the bibliographies of retrieved full texts of relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing oral or intravenous antibiotics versus placebo or no treatment to prevent infections in high-risk children aged 12 years and under. We used a combination of the Centers for Disease Control and Prevention (CDC), National Health Service (NHS), American Academy of Paediatrics (AAP) and National Institute for Health and Care Excellence (NICE) guidelines to define conditions at higher risk of complications. Our primary outcome was the incidence of bacterial lower respiratory infections. Secondary outcomes included clinical function, hospital admission, mortality, growth, use of secondary antibiotics, time off school or parental work, quality of life and adverse events. DATA COLLECTION AND ANALYSIS: We extracted data using a customised data extraction sheet, assessed the risk of bias of included studies using the Cochrane 'Risk of bias' criteria, and used the GRADE criteria to rate the quality of the evidence. We used a random-effects model for meta-analysis. We presented the results narratively where we could not statistically combine data. MAIN RESULTS: We included 10 RCTs of high-risk children using antibiotics (azithromycin, ciprofloxacin, co-trimoxazole, isoniazid, oral penicillin V or vancomycin) to prevent LRTIs. Three studies included HIV-infected children (n = 1345), four cystic fibrosis (n = 429) and one each sickle cell disease (n = 219), cancer (n = 160) and low birth weight neonates with underlying respiratory disorders (n = 40). The study duration ranged from seven days to three years. The quality of the evidence from studies including children with HIV infection, cystic fibrosis or cancer was moderate. Due to inadequate data, we were unable to rate the quality of the evidence for two studies: one in children with sickle cell disease (low risk of bias), and another in low birth weight neonates with underlying respiratory disorders (high risk of bias).In HIV-infected children receiving continuous isoniazid prophylaxis, there was no significant difference in the incidence of pulmonary tuberculosis (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.32 to 1.29, I(2) statistic = 47%, P value = 0.21). There was no significant effect on mortality with co-trimoxazole or isoniazid prophylaxis (RR 0.82, 0.46 to 1.46, I(2) statistic = 76%, P value = 0.58); however, analysis of one study that used co-trimoxazole showed a significant reduction in mortality (RR 0.67, 95% CI 0.53 to 0.85, P value = 0.001). There was a significant decrease in the rates of hospital admission per child-year of follow-up with co-trimoxazole prophylaxis in one study (P value = 0.01). There was no evidence of increased adverse events due to antibiotic prophylaxis (RR 1.10, 95% CI 0.75 to 1.64, I(2) statistic = 22%, P value = 0.28); however, there was scant reporting of antibiotic resistance - the one study that did assess this found no increase.In two studies of children with cystic fibrosis receiving ciprofloxacin prophylaxis, there was no significant difference in Pseudomonas infections (RR 0.76, 0.44 to 1.31, I(2) statistic = 0%, P value = 0.33). In two studies assessing the benefit of azithromycin prophylaxis, there was a significant reduction in the frequency of pulmonary exacerbations (RR 0.60, 95% CI 0.48 to 0.76, I(2) statistic = 0%, P value < 0.0001). The effect of antibiotic prophylaxis on growth in children with cystic fibrosis was inconsistent across the studies. There was an increased risk of emergence of pathogenic strains with either azithromycin or ciprofloxacin prophylaxis in two studies reporting this outcome. There was no significant difference in the quality of life (one study). In three studies, there was no significant increase in the frequency of adverse events with prophylaxis with azithromycin (two studies) or ciprofloxacin (one study). There was no evidence of increased antibiotic resistance in two studies.In the one study of children with sickle cell disease, a significantly lesser proportion of children with pneumococcal septicaemia was reported with penicillin V prophylaxis (P value = 0.0025).In the one study of children with cancer there was a significant decrease in Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole prophylaxis (RR 0.03, 95% CI 0.00 to 0.47, P value < 0.01). There was no significant increase in the frequency of adverse events with antibiotic prophylaxis.In low birth weight children with underlying respiratory disorders, there was no significant difference in the proportion of children with pulmonary infection with vancomycin prophylaxis (P value = 0.18).No included studies reported time off school or carer time off work. AUTHORS' CONCLUSIONS: There is inconclusive evidence that antibiotic prophylaxis in certain groups of high-risk children can reduce pneumonia, exacerbations, hospital admission and mortality in certain conditions. However, limitations in the evidence base mean more clinical trials assessing the effectiveness of antibiotics for preventing LRTIs in children at high risk should be conducted. Specifically, clinical trials assessing the effectiveness of antibiotics for preventing LRTIs in congenital heart disease, metabolic disease, endocrine and renal disorders, neurological disease or prematurity should be a priority.

A Comparison of Signals of Designated Medical Events and Non-designated Medical Events: Results from a Scoping Review.

INTRODUCTION AND OBJECTIVE: The European Medicines Agency (EMA) maintains a list of designated medical events (DMEs), events that are inherently serious and are prioritized for signal detection, irrespective of statistical criteria. We have analysed the results of our previously published scoping review to determine whether DME signals differ from those of other adverse events in terms of time to communication and characteristics of supporting reports of suspected adverse drug reactions. METHODS: For all signals, we obtained the launch year of medicinal products from textbooks or regulatory agencies, extracted the year of the first report in VigiBase and calculated the interval between the first report and communication (time to communication, TTC). We further retrieved the average completeness (via vigiGrade) of the reports in each case series in the years before the communication. We categorised as DME signals those concerning an event in the EMA's list. We described the two groups of signals using medians and interquartile ranges (IQR) and compared them using the Brunner-Munzel test, calculating 95% confidence intervals (95% CI) and P values. RESULTS: Of 4520 signals, 919 concerned DMEs and 3601 concerned non-DMEs. Signals of DMEs were supported by a median of 15 reports (IQR 6-38 reports) with a completeness score of 0.52 (IQR 0.43-0.62) and signals of non-DMEs by 20 reports (IQR 6-84 reports) with a completeness score of 0.46 (IQR 0.38-0.56). The probability that a random DME signal was supported by fewer reports than non-DME signals was 0.56 (95% CI 0.54-0.58, P < 0.001) and that of one having lower average completeness was 0.39 (95% CI 0.36-0.41, P < 0.001). The median TTCs of DME and non-DME signals did not differ (10 years), but the TTC was as low as 2 years when signals (irrespective of classification) were supported by reports whose average completeness was > 0.80. CONCLUSIONS: Signals of designated medical events were supported by fewer reports and higher completeness scores than signals of other adverse events. Although statistically significant, the differences in effect sizes between the two groups were small. This suggests that listing certain adverse events as DMEs is not having the expected effect of encouraging a focus on reports of the types of suspected adverse reactions that deserve special attention. Further enhancing the completeness of the reports of suspected adverse drug reactions supporting signals of designated medical events might shorten their time to communication and reduce the number of reports required to support them.

The Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Development and Statement.

BACKGROUND AND AIM: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts. METHODS: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting. RESULTS: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts. CONCLUSIONS: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence.

The REporting of A Disproportionality Analysis for DrUg Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Explanation and Elaboration.

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance.

Signals of Adverse Drug Reactions Communicated by Pharmacovigilance Stakeholders: A Scoping Review of the Global Literature.

INTRODUCTION AND OBJECTIVE: Signals of adverse drug reactions (ADRs) can be supported by reports of ADRs and by interventional and non-interventional studies. The evidence base and features of ADR reports that are used to support signals remain to be comprehensively described. To this end, we have undertaken a scoping review. METHODS: We searched the following databases: PubMed, EMBASE, PsycINFO, Web of Science, and Google Scholar, without language or time restrictions. We also hand searched the bibliographies of relevant studies. We included studies of any design if the results were described as signals. We assessed the levels of evidence using the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria and coded features of reports of ADRs using the Bradford Hill guidelines. RESULTS: Overall, 1974 publications reported 2421 studies of signals; 1683/2421 were clinical assessments of anecdotal reports of ADRs, but only 225 (13%) of these included explicit judgments on which features of the ADR reports were supportive of a signal. These 225 studies yielded 228 signals; these were supported by features, which were: 'experimental evidence' (i.e., positive dechallenge or rechallenge, 154 instances [68%]), 'temporality' (i.e., time to onset, 130 [57%]), 'exclusion of competing causes' (49 [21%]), and others (40 [17%]). Positive dechallenge/rechallenge often co-occurred with temporality (77/228). OCEBM 4 (i.e., case series and case-control studies) was the most frequent level of evidence (2078 studies). Between 2013 and 2019, there was a three-fold increase in clinical assessments of reports of ADRs compared with a less than two-fold increase in studies supported by higher levels of evidence (i.e., OCEBM 1-3). We identified an increased rate between 2013 and 2019 in disproportionality analyses (about 15 studies per year), mostly from academia. CONCLUSIONS: Most signals were supported by temporality and dechallenge/rechallenge, but clear reporting of judgments on causality remains infrequent. The number of studies supported only by anecdotal reports of ADRs increased from year to year. The impact of a growing number of signals of disproportionate reporting communicated without an accompanying clinical assessment should be evaluated.

Biomarkers of potential harm in people switching from smoking tobacco to exclusive e-cigarette use, dual use or abstinence: secondary analysis of Cochrane systematic review of trials of e-cigarettes for smoking cessation.

AIMS: This study aims to compare biomarkers of potential harm between people switching from smoking combustible cigarettes (CC) completely to electronic cigarettes (EC), continuing to smoke CC, using both EC and CC (dual users) and using neither (abstainers), based on behaviour during EC intervention studies. DESIGN: Secondary analysis following systematic review, incorporating inverse variance random-effects meta-analysis and effect direction plots. SETTING: This study was conducted in Greece, Italy, Poland, the United Kingdom and the United States. PARTICIPANTS: A total of 1299 adults smoking CC (nine studies) and provided EC. MEASUREMENTS: Measurements were conducted using carbon monoxide (CO) and 26 other biomarkers. FINDINGS: In pooled analyses, exhaled CO (eCO) was lower in EC versus EC + CC [mean difference (MD) = -4.40 parts per million (p.p.m.), 95% confidence interval (CI) = -12.04 to 3.24, two studies] and CC (MD = -9.57 p.p.m., 95% CI = -17.30 to -1.83, three studies). eCO was lower in dual users versus CC only (MD = -1.91 p.p.m., 95% CI = -3.38 to -0.45, two studies). Magnitude rather than direction of effect drove substantial statistical heterogeneity. Effect direction plots were used for other biomarkers. Comparing EC with CC, 12 of 13 biomarkers were significantly lower in EC users, with no difference for the 13th. Comparing EC with dual users, 12 of the 25 biomarkers were lower for EC, and five were lower for dual use. For the remaining eight measures, single studies did not detect statistically significant differences, or the multiple studies contributing to the outcome had inconsistent results. Only one study provided data comparing dual use with CC; of the 13 biomarkers measured, 12 were significantly lower in the dual use group, with no statistically significant difference detected for the 13th. Only one study provided data on abstainers. CONCLUSIONS: Switching from smoking to vaping or dual use appears to reduce levels of biomarkers of potential harm significantly.

Coinfection with Strongyloides and SARS-CoV-2: A Systematic Review.

BACKGROUND: Treatments for COVID-19, including steroids, might exacerbate Strongyloides disease in patients with coinfection. We aimed to systematically review clinical and laboratory features of SARS-CoV-2 and Strongyloides coinfection, investigate possible interventions, assess outcomes, and identify research gaps requiring further attention. METHODS: We searched two electronic databases, LitCOVID and WHO, up to August 2022, including SARS-CoV-2 and Strongyloides coinfection studies. We adapted the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment to evaluate if using corticosteroids or other immunosuppressive drugs in COVID-19 patients determined acute manifestations of strongyloidiasis. RESULTS: We included 16 studies reporting 25 cases of Strongyloides and SARS-CoV-2 coinfection: 4 with hyperinfection syndrome; 2 with disseminated strongyloidiasis; 3 with cutaneous reactivation of strongyloidiasis; 3 with isolated digestive symptoms; and 2 with solely eosinophilia, without clinical manifestations. Eleven patients were asymptomatic regarding strongyloidiasis. Eosinopenia or normal eosinophil count was reported in 58.3% of patients with Strongyloides reactivation. Steroids were given to 18/21 (85.7%) cases. A total of 4 patients (19.1%) received tocilizumab and/or Anakirna in addition to steroids. Moreover, 2 patients (9.5%) did not receive any COVID-19 treatment. The causal relationship between Strongyloides reactivation and COVID-19 treatments was considered certain (4% of cases), probable (20% of patients), and possible (20% of patients). For 8% of cases, it was considered unlikely that COVID-19 treatment was associated with strongyloidiasis reactivations; the relationship between the Strongyloides infection and administration of COVID-19 treatment was unassessable/unclassifiable in 48% of cases. Of 13 assessable cases, 11 (84.6%) were considered to be causally associated with Strongyloides, ranging from certain to possible. CONCLUSIONS: Further research is needed to assess the frequency and risk of Strongyloides reactivation in SARS-CoV-2 infection. Our limited data using causality assessment supports recommendations that clinicians should screen and treat for Strongyloides infection in patients with coinfection who receive immunosuppressive COVID-19 therapies. In addition, the male gender and older age (over 50 years) may be predisposing factors for Strongyloides reactivation. Standardized guidelines should be developed for reporting future research.